Serotonin (5-hydroxytryptamine, 5-HT) plays a significant role in influencing a large number of central and peripheral processes. 5-HT-selective pharmacotherapies have been developed to treat a wide variety of medical problems including depression, anxiety, schizophrenia, migraine, emesis, and appetite control (Annual Reports in Medicinal Chemistry, Volume 32, 2002, Academic Press, Fitzgerald, L., Ennis, M. “5-HT2C Receptor Modulators: Progress in Development of New CNS Medicines” pp 21-30). 5-HT exerts its influence through activation of fourteen distinct receptor subtypes in seven separate families (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7).
Each of the seven families may also encompass various subtypes. For example, the 5-HT1 family includes subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. The 5-HT2 family includes 5-HT2A, 5-HT2B and 5-HT2C. Lastly, the 5-HT3 family includes 5-HT3A and 5-HT3B while the 5-HT5 family includes 5-HT5A. While the 5-HT1, 5-HT2 and 5-HT3 families have been studied most extensively, each family has been linked to various disease indications as discussed below.
Modulation of the 5-HT family of receptors has been shown to play a role in numerous human diseases including obesity, obsessive-compulsive disorder (OCD), sexual dysfunction, epilepsy, schizophrenia, and anxiety disorders (Roth, B., Shapiro, D. “Insights into the Structure and Function of 5-HT2 Family Serotonin Receptors Reveal Novel Strategies for Therapeutic Target Development” Expert Opin. Ther. Targets 2001, 5, 685; Martin, J., Bos, M., Jenck, F., Moreau, J-l., Mutel, V., Sleight, A., Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G., Kohler, C., van Delft, A. “5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential” J. Pharm. Experimental Ther. 1998, 286, 913; Tecott, L., Sun, L., Akana, S., Strack, A., Lowenstein, D., Dallman, M., Julius, D. “Eating Disorder and Epilepsy in Mice Lacking 5-HT2C Serotonin Receptors” Nature 1995, 374, 542). A clinical study in 1997 (Sargent, P., Sharpley, A., Williams, C., Cowen, P. “5-HT2C-Receptor Activation Decreases Appetite and Body Weight in Obese Subjects” Psychopharmacology 1997, 133, 309; Barnes, Nicholas M., Sharp, Trevor “A Review of Central 5-HT Receptors and Their Function” Neuropharmacology 1999, 38, 1038). However, a need for potent and selective 5-HT modulators (specifically those associated with 5-HT2A, 5-HT2C and 5-HT6) still exists